Peptic ulcer disease exists in two forms, duodenal ulcers and gastric ulcers. Central to the cause of duodenal ulcers, is the production of excess stomach acid and pepsin and a rapid gastric emptying tire. This results in an increase in duodenal exposure to secreted acid and enzymes, and in mucosal damage.
The second form of the disorder, gastric ulcer disease, may be caused by increased stomach acid and a breakdown of the complex stomach defenses that normally protect the gastric mucosa from acid damage. Although the two conditions have different etiologies, both benefit from a reduction in gastric acid secretion.
Because excess stomach acid is a central cause of ulcers, antacid preparations are commonly used as one method of treatment. This method merely neutralizes stomach acid after it is produced. Consequently, large quantities of antacids must be consumed on an ongoing basis to neutralize acid which is continually produced in the stomach. Antacids do not cure the disease because they do not affect the source of acid production.
Gastric acid is produced in a specialized stomach cell, the parietal cell. Parietal cells can be stimulated to secrete acid by acetylcholine, histamine and gastrin, upon the binding of each of these compounds with specific receptors on the surface of the cell. Of these the most potent stimulator of acid secretion is the peptide hormone gastrin.
Current approaches to the control and cure of peptic ulcers center upon devising drugs that inhibit the ability of one or more of these compounds to stimulate acid production or secretion. The most effective group of drugs approved for sale are the H2 antagonists (e.g. TAGAMET and ZANTAC) which block the histamine H2 receptors on gastric parietal cells and inhibit acid secretion. These drugs, however, require relatively large doses on a daily basis and may induce several undesirable side effects. In cases where H2 antagonists have cured ulcers, relapses occur in almost 100% of cured individuals within a year of discontinuation of treatment. Other drugs have also exhibited problems, including low efficacy and unacceptable levels of toxicity. In the case the peptide hormone gastrin, no successful chemical antagonists have been identified.
Gastrin has several important functions in the gastrointestinal tract, the two most important being stimulation of acid secretion and stimulation of the growth of cells in the gastrointestinal tract. The hormone exists in at least two molecular forms, heptadecagastrin (“G17”) and tetratriacontagastrin (“G34”) named according to the number of amino acid (“AA”) residues in each molecule. G34 and G17 are identical in structure at the carboxy terminus, which is the binding site of the hormones with receptors. G17 constitutes the 17 carboxy terminal (“C-terminal”) end residues of G34. G34 consists of the 17 C-Terminal end residues which comprise G17 and an additional different amino acid sequence of 17 amino terminal (“N-terminal”) residues. When G34 is split by trypsin a G17 subunit and a non-hormonal 17 amino acid subunit results. Though G17 is usually obtained by trypsin cleavage of G34, each form may also be generated separately from its own prohormone.
Although G17 and G34 are thought to be equipotent on a molar basis as stimulators of acid release, G34 is most probably responsible for the stimulation of growth of the gastrointestinal mucosa and the maintenance of the basal acidity of the stomach. G34 is the principal form present during interdigestive periods. G34 has a serum half life approximately six times as long as G17 (40 minutes versus 6 minutes) and is produced in both the stomach and the duodenum. Alternatively, G17 is the primary stimulator of real induced gastric acid secretion. G17 is 1500 times more potent than histamine and makes up 90% of the antral (stomach) gastrin. G17 accounts for roughly 60%-70% of the gastrin-mediated acid release.
The prior art in the area of gastrin immunology mainly concerns the induction of antibodies useful for identifying anatomic sites containing or producing gastrin G17 or G34 in laboratory animals; see Sugano, K., et al., 1985, “Identification and characterization of glycine-extended post translational processing intermediates of progastrin in porcine stomach”, J. of Biological Chemistry 250: 11724-11729; Vaillant, C., et al., 1979, “Cellular origins of different forms of gastrin: The specific immunocytochemical localization of related peptides. J. Histochem, Cytochem 27:932-935; Larsson, L. I. et al., 1977, “Characterization of antral gastrin cells with region-specific antisera”. J. Histochem. Cytochem 25: 1317-1321. The antisera reported in these publications contained antibodies of numerous specificities, for a variety of antigenic epitopes on gastrin molecules.
Attempts to control gastrin levels by anti-gastrin antibodies induced by active immunization or passive administration of preformed antibodies such as those reported in Jaffe, B. M., et al., 1971, “Gastrin resistance following immunizations to the C-terminal tetrapeptide amide of gastrin, Surgery 69: 232-238: Jaffe, B. M., et al., 1970, “Inhibition of endogenous gastrin activity by antibodies to the carboxyl terminal tetrapeptide amide of gastrin”, Gastroenterology 58: 151-156; Jaffe et al., 1969, “Inhibition of endogenous gastrin activity by incubation with antibodies to the C-terminal tetrapeptide of gastrin. Surgery 65: 5633-639 are different from the present invention in that the immunogen used was derived from the carboxyl terminal tetra-peptide amino acid sequence common to G17, G34, and to another important hormone, cholecystokinin (“CCK”). The immunogen of Jaffe et al. is thus of no practical value as an anti-gastrin vaccine component; on the contrary, it would produce a deleterious state in which all gastrin activity and other hormone function of G17, G34, together with CCK, would be blocked and eliminated by immunization.
This invention provides a novel immunological approach to the control and regulation of gastrin induced disorders such as peptic ulcers. According to the invention, antibodies are induced in the patient by active immunization with immunogens that selectively target specific forms of gastrin. Alternatively, the patient can be passively immunized with anti-gastrin antibodies specific for certain forms of gastrin.
In addition to peptic uclers, other diseases appear to be related to the hormonal and stimulatory effects of gastrin. These diseases may also be treated by the selective anti-gastrin treatment of the invention.
An area of major medical importance for which the neutralization of gastrin hormonal activity has great therapeutic potential concerns the control of tumors and pathological conditions that are stimulated by gastrointestinal hormones. Several cancers of the gastrointestinal tract and associated tissues are stimulated to grow by the trophic action of gastrin. See Lamers, C. S. H. S., and Jansen, J. B. M. S., 1988, “Role of Gastrin and Cholecystokinin in Tumours of the Gastrointestinal Tract”, Eur. J. Cancer Clin. Oncol. 22: 267-273. Gastrin promotes the growth of colon carcinoma, gastric carcinoma and gastric carcinoids. Gastrin antagonists may inhibit the growth of human colon cancer and enhance host survival as has been shown in mice; see, Beauchamp, R. O., et. al. 1985, “Proglumide, A Gastrin Receptor Antagonist, Inhibits Growth Of Colon Cancer And Enhances Survival In Mice.” Ann. Surg. 202: 303-309. The neutralization of gastrin tumor promoting activity may provide.an important therapy for these diseases.
A second important application of gastrin neutralization therapy concerns conditions in which the hormone is overproduced. Certain cancers of the gastrointestinal tract, apudomas, produce extremely large quantities of gastrin. In either case, the excess hormone produced by the apudoma or pituitary tumor will have adverse physiologic effects on organs or tissues containing receptors for the hormone. Excess gastrin production by apudomas stimulates hypertrophy of the acid secreting epithelium of the stomach, leading to excess stomach acid secretion, peptic ulcer, and neoplastic changes in the epithelium.
Available treatment for tumors stimulated by gastrin and for tumors that produce gastrin consists primarily of surgical resection of the cancerous tissue. This approach is frequently unsuccessful; in many instances the tumors cannot be located or are present in anatomic sites that are inoperable. In most instances these tumors do not respond well to radiation or chemotherapy regimens. New treatments are needed to supplement present procedures.
A therapeutic method of selectively neutralizing the biological activity of these hormones would provide an effective means of controlling or preventing the pathologic changes resulting from excessive hormone production.
The method of cancer therapy described in this invention has several advantages over present treatment methods. The method is non-invasive, selectively reversible, does not damage normal tissue, does not require frequent repeated treatments, does not cross the blood brain barrier and has reduced side effects.
The therapy may be selectively reversed by injecting the patient with a pharmaceutical composition comprising a neutralizing epitope molecule. This molecule should comprise the epitope sequence free of an immunogenic carrier. This non-immunogenic molecule will bind to the free antibodies previously induced against the epitope in the host.